This project seeks to improve the clinical care available to patients with disorders of ovarian follicle function and ovulation through research using animal models and clinical protocols. In pursuing this goal, we expect to expand understanding of the ovarian follicle in health and disease. We have focused on premature ovarian failure, a condition that prematurely terminates ovarian function and fertility in 1% of women. We have found that femoral neck bone density is significantly reduced in women with premature ovarian failure. Surprisingly, more than one-half of our patients had a bone density low enough to cause a threefold increase their risk of fracture. Inappropriate luteinization of graafian follicles appears to be a major pathophysiologic mechanism in patients with karyotypically normal spontaneous premature ovarian failure. Strikingly, we found luteinized graafian follicles in all the antral follicles we biopsied in 6 patients with karyotypically normal spontaneous premature ovarian failure. Therefore, luteinized graafian follicles account for at least 60% of the antral structures imaged (95% confidence limit). We have particular interest in autoimmune ovarian failure. Using an animal model, we found that autoantibodies from mice with experimental autoimmune oophoritis bind to a 120 kd protein that is specific to the oocyte cytoplasm. By screening a mouse ovarian cDNA expression library with this serum, we identified a novel oocyte-specific gene that may represent the inciting antigen in this disease. By using transgenic technology we will investigate the function of this novel gene, and determine if the novel oocyte-specific-expression gene produces the inciting ovarian antigen in murine experimental autoimmune oophoritis. Future clinical directions involve developing strategies to increase bone density in women with premature ovarian failure and a treatment to prevent inappropriate follicle luteinization in patients with premature ovarian failure. We will also expand our efforts to include a clinical study of polycystic ovary syndrome. We have initiated a treatment protocol to test the hypothesis that the hyperandrogenism associated with polycystic ovary syndrome impairs follicular development by a receptor-mediated mechanism.